The present invention relates to compounds that are shown to be potent cyclin/cyclin dependent kinase (cdk) inhibitors. Compounds with these properties are shown to be potent inhibitors of cell growth and proliferation. Such compounds can be used to treat the following conditions in mammals: rheumatoid arthritis, lupus, type 1 diabetes, multiple sclerosis, cancer, restenosis, gout and other proliferative diseases involving elevated levels of cell proliferation compared to healthy mammals. Compounds of the present invention which are biaryl substituted purine derivatives are shown to be potent antiproliferative agents against a number of human transformed cell lines, and also inhibitors of human cyclin/cdk kinase complexes.
Cellular Proliferation and Cancer.
The disruption of external or internal regulation of cellular growth can lead to uncontrolled proliferation and in cancer, tumor formation. This loss of control can occur at many levels and, indeed, does occur at multiple levels in most tumors. Further, although tumor cells can no longer control their own proliferation, they still must use the same basic cellular machinery employed by normal cells to drive their growth and replication.
Cyclin Dependent Kinases and Cell Cycle Regulation.
Progression of the normal cell cycle from the G1 to S phase, and from the G2 phase to M phase is dependent on cdks (Sherr, C. J., Science 274:1672-1677 (1996)). Like other kinases, cdks regulate molecular events in the cell by facilitating the transfer of the terminal phosphate of adenosine triphosphate (ATP) to a substrate protein. Isolated cdks require association with a second subunit, called cyclins (Desai et al., Mol. Cell. Biol., 15:345-350 (1995)). Cyclins cause conformational changes at the cdk active site, allowing ATP access and interaction with the substrate protein.
The balance between its rates of synthesis and degradation controls the level of each cyclin at any point in the cycle (Elledge, S. J., et al., Biochim. Biophys. Acta, 1377:M61-M70 (1998)). The influences of cyclin/cdk activity on the cell cycle and cellular transformation are summarized in Table 1.
Abnormal Cyclin/cdk Activity in Cancer.
In a normal cell, interlocking pathways respond to the cell""s external environment and internal checkpoints monitor conditions within the cell to control the activity of cyclin/cdk complexes. A reasonable hypothesis is that the disruption of normal control of cyclin/cdk activity may result in uncontrolled proliferation. This hypothesis appears to hold in a number of tumor types in which cyclins are expressed at elevated levels (Table 1). Mutations in the genes encoding negative regulators (proteins) of cyclin/cdk activity are also found in tumors (Larsen, C.-J., Prop. Cell Cycle Res., 3:109-124 (1997)); (Kamb, A., Trends in Genetics, 11:136-140 (1995)). Members of the Cip family of cdk inhibitors form a ternary complex with the cyclin/cdk and require binding to cyclinA, cyclinE, or cyclinD (Hall, M., et al., Oncogene, 11:1581-1588 (1995)). In contrast, Ink family members form a binary complex with cdk4 or cdk6 and prevent binding to cyclinD (Parry, D.; et al., EMBO J., 14:503-511 (1995)).
Inhibitors of Cyclin/cdk Complexes as Potential Anticancer Agents.
Tumors with elevated cyclin/cdk activity, whether from the over expression of cyclins or the loss of an endogenous cdk inhibitor, are prime targets for potential therapies based on small molecule cyclin/cdk inhibitors. In fact, several small molecule inhibitors of cyclin/cdks are reported (Meijer, L., et al., xe2x80x9cProgress in Cell Cycle Research,xe2x80x9d Plenum Press: New York, 351-363 (1995)) and appear to bind at the ATP site of the kinase. Some information is known about small molecule inhibitors of other kinases, such as PKC (serine kinase) (Murray, K. J. et al., xe2x80x9cAnn. Rep. Med. Chem.,xe2x80x9d J. Bristol, Ed., Academic Press, Inc.: New York, Chapter 26 (1994)) and tyrosine kinases (Fantl, W. J., et al., Ann. Rev. Biochem., 62:453 (1993); Burke, T. R., Drugs of the Future, 17:119-1131 (1992); Dobrusin, E. M. et al., xe2x80x9cAnn. Rep. Med. Chem,xe2x80x9d J. Bristol, Ed., Academic Press Inc.: New York, Chapter 18 (1992); Spence, P., Curr. Opin. Ther. Patents, 3:3 (1993)). A number of known inhibitors were obtained from commercial sources or were synthesized by literature procedures.
Purine Compounds as Cyclin/cdk Inhibitors.
There are several reports of 2,6-diamino substituted purine derivatives as cyclin/cdk inhibitors and as inhibitors of cellular proliferation. Among those are reports by U.S. Pat. No. 5,583,137 to Coe, et al., olomoucine (Vesely, J., et al., Eur. J. Biochem., 224:771-786 (1994)), roscovitine (Meijer, L., Eur. J. Biochem., 243:527-536 (1997)), WO 97/16452 to Zimmerman, Imbach, P., et al., Bioorg. Med. Chem. Lett., 9:91-96 (1999), Norman, T. C., et al., J. Amer. Chem. Soc., 118:7430-7431 (1996), Gray, N. S., et al., Tetrahedron Lett., 38:1161-1164 (1997), Gray, N. S., et al., Science, 281:533-538 (1998), WO 98/05335 to Lum, et al., Schow, S. R., et al., Bioorg. Med. Chem. Lett, 7:2697-2702 (1997), U.S. Pat. No., 5,886,702 to Mackman, et al., Nugiel, D. A., et al., J. Org. Chem., 62:201-203 (1997), and Fiorini, M. T. et al., Tetrahedron Lett, 39:1827-1830 (1998). Many of these reported compounds are shown to inhibit cyclin/cdk complexes and have modest cellular proliferation inhibition properties.
The compounds of the present invention are shown to have far superior biological activities as cyclin/cdk complex inhibitors as well as inhibitors of cellular proliferation compared to those previously reported. In fact, the art (e.g., Fiorini, M. T. et al., Tetrahedron Lett, 39:1827-1830 (1998)) teaches away from compounds of this invention, claiming lack of cellular proliferation inhibition.
The compounds of the present invention are 2,6,9-trisubstituted purine derivatives which are inhibitors of cyclin/cdk complexes. The compounds of the current invention also are potent inhibitors of human cellular proliferation. As such, the compounds of the present invention constitute pharmaceutical compositions with a pharmaceutically acceptable carrier. Such compounds are useful in treating conditions in a mammal mediated by elevated levels of cell proliferation compared to a healthy mammal by administering to such mammal an effective amount of the compound.
In one embodiment, the compounds of the present invention are represented by the chemical structure found in Formula I 
wherein:
R1 are the same or different and independently selected from the group consisting of:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3; and
CH(CF3)2;
the combination of X, D, and Q are either:
Dxe2x95x90Qxe2x95x90N, and Xxe2x95x90CH; or
Dxe2x95x90Xxe2x95x90N, and Qxe2x95x90CH; or
Qxe2x95x90Xxe2x95x90N, and Dxe2x95x90CH; or
Qxe2x95x90N, and Dxe2x95x90Xxe2x95x90CH;
Vxe2x95x90NH;
O;
S; or
CH2;
R2=phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, and C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R1, and C(O)CH3;
R3 are the same or different and independently selected from the group consisting of:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; and
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined
above in R2;
R4=H;
C1-C4-straight chain alkyl; or
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;
n1=0-3;
n=0-3;
A=CH2;
(CH2)2;
(CH2)3;
OCH2CH2; or
CHCH3;
Y=H;
OR1;
N(R1)2;
N(R1)C(O)R3;
N(R1)C(O)R5;
N(R1)C(O)CH(R6)NH2;
N(R1)SO2R3;
N(R1)C(O)NHR3; or
N(R1)C(O)OR6;
R5=C3-C7-cycloalkyl;
R6=C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; or
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
or a pharmaceutically acceptable salt thereof.
Another aspect of the present invention is directed to a compound of the following formula: 
wherein:
R1 are the same or different and independently selected from the group consisting of:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3; and
CH(CF3)2;
the combination of X, D, and Q are either:
Dxe2x95x90Qxe2x95x90N, and Xxe2x95x90CH; or
Qxe2x95x90Xxe2x95x90N, and Qxe2x95x90CH; or
Qxe2x95x90Xxe2x95x90N, and Dxe2x95x90CH; or
Qxe2x95x90N, and Dxe2x95x90Xxe2x95x90CH;
V=NH;
O;
S; or
CH2;
R2=phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, and C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R1, and C(O)CH3;
n=0-3;
A=CH2;
(CH2)2;
(CH2)3;
OCH2CH2; or
CHCH3;
Y=H;
OR1;
N(R1)2;
N(R1)C(O)R3;
N(R1)C(O)R5;
N(R1)C(O)CH(R6)NH2;
N(R1)SO2R3;
N(R1)C(O)NHR3; or
N(R1)C(O)OR6;
R3 are the same or different and independently selected from the group consisting of:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; and
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R5=C3-C7-cycloalkyl;
R6=C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl; or
C2-C4-alkenyl chain;
or a pharmaceutically acceptable salt thereof.
The present invention is also directed to a process for preparation of a purine derivative compound of the formula: 
wherein:
R1 are the same or different and independently selected from the group consisting of:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3; and
CH(CF3)2;
the combination of X, D, and Q are either:
Dxe2x95x90Qxe2x95x90N, and Xxe2x95x90CH; or
Dxe2x95x90Xxe2x95x90N, and Qxe2x95x90CH; or
Qxe2x95x90Xxe2x95x90N, and Dxe2x95x90CH; or
Qxe2x95x90N, and Dxe2x95x90Xxe2x95x90CH;
V=NH;
O;
S; or
CH2;
R2=phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, and C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R1, and C(O)CH3;
R3 are the same or different and independently selected from the groug consisting of:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; and
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
C1-C4-straight chain alkyl; or
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;
n1=0-3;
n=0-3;
A=CH2;
(CH2)3;
OCH2CH2; or
CHCH3;
Y=H;
OR1;
N(R1)2;
N(R1)C(O)R3;
N(R1)C(O)R5;
N(R1)C(O)CH(R6)NH2;
N(R1)SO2R3;
N(R1)C(O)NHR3; or
N(R1)C(O)OR6;
R5=C3-C7-cycloalkyl;
R6=C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; or
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
or a pharmaceutically acceptable salt thereof, said process comprising:
reacting a first intermediate compound of the formula: 
xe2x80x83where Z=Br or I
xe2x80x83with a compound of the formula: R2xe2x80x94B(OH)2, R2xe2x80x94Sn(n-Bu)3, or R2xe2x80x94Sn(Me)3, or mixtures thereof, under conditions effective to form the purine derivative compound.
Another aspect of the present invention is directed to a process for preparation of a purine derivative compound of the formula: 
wherein:
R1 are the same or different and independently selected from the group consisting of:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3; and
CH(CF3)2;
the combination of X, D, and Q are either:
Dxe2x95x90Qxe2x95x90N, and Xxe2x95x90CH; or
Dxe2x95x90Xxe2x95x90N, and Qxe2x95x90CH; or
Qxe2x95x90Xxe2x95x90N, and Dxe2x95x90CH; or
Qxe2x95x90N, and Dxe2x95x90Xxe2x95x90CH;
V=NH;
O;
S; or
CH2;
R2=phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, and C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R1, and C(O)CH3;
R3 are the same or different and independently selected from the group consisting of:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; and
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R1=H;
C1-C4-straight chain alkyl; or
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;
n1=0-3;
n=0-3;
A=CH2;
(CH2)2;
(CH2)3;
OCH2CH2; or
CHCH3;
Y=H;
OR1;
N(R1)2;
N(R1)C(O)R3;
N(R1)C(O)R5;
N(R1)C(O)CH(R6)NH2;
N(R1)SO2R3;
N(R1)C(O)NHR3; or
N(R1)C(O)OR6;
R5=C3-C7-cycloalkyl;
R6=C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
CH2)nPh or
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
or a pharmaceutically acceptable salt thereof, said process comprising:
reacting a first intermediate compound of the formula: 
xe2x80x83under reductive or hydrogenation conditions effective to form the purine derivative compound.
Another aspect of the present invention is directed to a process for preparation of a purine derivative compound of the formula: 
wherein:
R1 are the same or different and independently selected from the group consisting of:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3; and
CH(CF3)2;
the combination of X, D, and Q are either:
Dxe2x95x90Qxe2x95x90N, and Xxe2x95x90CH; or
Dxe2x95x90Xxe2x95x90N, and Qxe2x95x90CH; or
Qxe2x95x90Xxe2x95x90N, and Dxe2x95x90CH; or
Qxe2x95x90N, and Dxe2x95x90Xxe2x95x90CH;
V=NH;
O;
S; or
CH2;
R2=phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, and C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R1, and C(O)CH3;
R3 are the same or different and independently selected from the group consisting of:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; and
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=H;
C1-C4-straight chain alkyl; or
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;
n1=0-3;
n=0-3;
A=CH2;
(CH2)2;
(CH2)3;
OCH2CH2; or
CHCH3;
Y=H;
OR1;
N(R1)2;
N(R1)C(O)R3;
N(R1)C(O)R5;
N(R1)C(O)CH(R6)NH2;
N(R1)SO2R3;
N(R1)C(O)NHR3; or
N(R1)C(O)OR6;
R5=C3-C7-cycloalkyl;
R6=C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; or
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
or a pharmaceutically acceptable salt thereof, said process comprising:
reacting a first intermediate compound of the formula: 
xe2x80x83with a compound of the formula: 
xe2x80x83where V1=NH2;
OH; or
SH;
xe2x80x83under conditions effective to form the purine derivative compound.
Another aspect of the present invention is directed to a process for preparation of a purine derivative compound of the formula: 
wherein:
R1 are the same or different and independently selected from the group consisting of:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3; and
CH(CF3)2;
the combination of X, D, and Q are either:
Dxe2x95x90Qxe2x95x90N and Xxe2x95x90CH; or
Dxe2x95x90Xxe2x95x90N and Qxe2x95x90CH; or
Qxe2x95x90Xxe2x95x90N and Dxe2x95x90CH; or
Qxe2x95x90N and Dxe2x95x90Xxe2x95x90CH;
V=NH;
O;
S; or
CH2;
R2=phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, and C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R1, and C(O)CH3;
R3 are the same or different and independently selected from the group consisting of:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; and
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=H;
C1-C4-straight chain alkyl; or
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;
n1=0-3;
n=0-3;
A=CH2;
(CH2)2;
(CH2)3;
OCH2CH2; or
CHCH3;
Y=NR1C(O)R3;
NR1C(O)R5;
NR1SO2R3;
NR1C(O)NHR3;or
NR1C(O)OR6 
R5=C3-C7-cycloalkyl;
R6=C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
CH2)nPh; or
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
or a pharmaceutically acceptable salt thereof;
said process comprising:
reacting a first intermediate compound having the same formula as the purine derivative compound except that Y=NHR1, with R3COCl or R5COCl or R3SO2Cl or R3NCO or R6OC(O)Cl under conditions effective to form the purine derivative compound.
Yet another aspect of the present invention is directed to a process for preparation of a purine derivative compound of the formula: 
wherein:
R1 are the same or different and independently selected from the group consisting of:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3; and
CH(CF3)2;
the combination of X, D, and Q are either:
Dxe2x95x90Qxe2x95x90N and Xxe2x95x90CH; or
Dxe2x95x90Xxe2x95x90N and Qxe2x95x90CH; or
Qxe2x95x90Xxe2x95x90N and Dxe2x95x90CH; or
Qxe2x95x90N and Dxe2x95x90Xxe2x95x90CH;
V=NH;
O;
S; or
CH2;
R2=phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, and C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R1, and C(O)CH3;
R3 are the same or different and independently selected from the group consisting of:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; and
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=H;
C1-C4-straight chain alkyl; or
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;
n1=0-3;
n=0-3;
A=CH2;
(CH2)2;
(CH2)3;
OCH2CH2; or
CHCH3;
Y=NHC(O)CH(R6)NH2,
R5=C3-C7-cycloalkyl;
R6=C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; or
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
or a pharmaceutically acceptable salt thereof;
said process comprising:
reacting a first intermediate compound having the same formula as the purine derivative compound except that Y is NH2, with a compound of the formula: PNHCH(R6)CO2H under conditions effective to form the purine derivative compound after a suitable deprotection strategy,
wherein
P=C(O)OtBu;
C(O)OCH2Ph;
9-Fluorenylmethyl Carbamate (Fmoc);
Benzyl; or
Alkyl Carbamate (Alloc).
The compounds of the present invention, as described in Formula I, show significantly improved growth inhibition of human transformed cell lines and/or cyclin/cdk inhibition relative to compounds of the prior art. These compounds have been demonstrated to be potent growth inhibitors in dozens of human transformed cell lines. Olomoucine, a structurally related purine derivative, is a poor human transformed cell growth inhibition agent with GI50 values in the 20,000-100,000 nM range over 60-transformed cell lines. By contrast, the compounds of the present invention demonstrate GI50 values over 60-transformed cell lines in the  less than 10-25,000 nM range, preferably in the  less than 10-100 nM range over 60-transformed cell lines, and, most preferably,  less than 10 nM across 60-human transformed cell lines. This finding is unexpected from the prior art, which specifically teaches that compounds of the present invention would not be potent human transformed cell line growth inhibitors.
The R2 group in Formula I imparts unexpected and significant improvement in growth inhibition in human transformed cell lines, while substitution of various groups at R3 and R4 found in Formula I impart important features that contribute to cyclin/cdk inhibition and growth inhibition of human transformed cell lines. Specifically, the combination of the R2 group and the substitutions within R3 and R4 result in compounds with superior biological activity. Compounds which are cyclin/cdk inhibitors and/or human transformed cell line growth inhibitors have utility in treating human proliferative cellular disorders.
The compounds of the present invention are represented by the chemical structure found in Formula I. 
wherein:
R1 are the same or different and independently selected from the group consisting of:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3; and
CH(CF3)2;
the combination of X, D, and Q are either:
Dxe2x95x90Qxe2x95x90N, and Xxe2x95x90CH; or
Dxe2x95x90Xxe2x95x90N, and Qxe2x95x90CH; or
Qxe2x95x90Xxe2x95x90N, and Dxe2x95x90CH; or
Qxe2x95x90N, and Dxe2x95x90Xxe2x95x90CH;
V=NH;
O;
S; or
CH2;
R2=phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, and C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R1, and C(O)CH3;
R3 are the same or different and independently selected from the group consisting of:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; and
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=H;
C1-C4-straight chain alkyl; or
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form with intervening atoms a 5-8-membered saturated or unsaturated ring;
n1=0-3;
n=0-3;
A=CH2;
(CH2)2;
(CH2)3;
OCH2CH2; or
CHCH3;
Y=H;
OR1;
N(R1)2;
N(R1)C(O)R3;
N(R1)C(O)R5;
N(R1)C(O)CH(R6)NH2;
N(R1)SO2R3;
N(R1)C(O)NHR3; or
N(R1)C(O)OR6;
R5=C3-C7-cycloalkyl;
R6=C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; or
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
or a pharmaceutically acceptable salt thereof.
More preferably, the compounds of the current invention are represented by the chemical structure found in Formula III. 
wherein:
R1 are the same or different and independently selected from the group consisting of:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3; and
CH(CF3)2;
the combination of X, D, and Q are either:
Dxe2x95x90Qxe2x95x90N, and Xxe2x95x90CH; or
Dxe2x95x90Xxe2x95x90N, and Qxe2x95x90CH; or
Qxe2x95x90Xxe2x95x90N, and Dxe2x95x90CH; or
Qxe2x95x90N, and Dxe2x95x90Xxe2x95x90CH;
V=NH;
O;
S; or
CH2;
R2=phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, and C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles selected from the group consisting of:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl; and
4-isoquinolinyl; or
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from the group consisting of Br, Cl, F, R1, and C(O)CH3;
n=0-3;
A=CH2;
(CH2)2;
(CH2)3;
OCH2CH2; or
CHCH3;
Y=H;
OR1;
N(R1)2;
N(R1)C(O)R3;
N(R1)C(O)R5;
N(R1)C(O)CH(R6)NH2;
N(R1)SO2R3;
N(R1)C(O)NHR3; or
N(R1)C(O)OR6;
R3 are the same or different and independently selected from the group consisting of:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh; and
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R5=C3-C7-cycloalkyl;
R6 =C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl; or
C2-C4-alkenyl chain;
or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention is directed to a method of treating a mammal with a disorder mediated by elevated levels of cellular proliferation comprising administering a therapeutically effective amount of the compound of the present invention to the mammal under conditions effective to treat the disorder mediated by elevated levels of cell proliferation.
The compounds of the present invention can be administered orally, parenterally, for example, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes. They may be administered alone or with suitable pharmaceutical carriers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions, or emulsions.
Based on the results obtained in the standard pharmacological test procedures described below, the compounds of the present invention are useful as antineoplastic agents. More particularly, the compounds of the present invention are useful for inhibiting the growth of neoplastic cells, causing cell death of neoplastic cells, and eradicating neoplastic cells. The compounds of the present invention are, therefore, useful for treating solid tumors, including sarcomas and carcinomas, such as astrocytomas, prostate cancer, breast cancer, small cell lung cancer, and ovarian cancer, leukemias, lymphomas, adult T-cell leukemia/lymphoma, and other neoplastic disease states.
In addition to the utilities described above, many of the compounds of the present invention are useful in the preparation of other compounds.
The active compounds of the present invention may be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, these active compounds may be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compound in these compositions may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions according to the present invention are prepared so that an oral dosage unit contains between about 1 and 250 mg of active compound.
The tablets, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar, or both. A syrup may contain, in addition to active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor.
These active compounds may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The compounds of the present invention may also be administered directly to the airways in the form of an aerosol. For use as aerosols, the compounds of the present invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants. The materials of the present invention also may be administered in a non-pressurized form such as in a nebulizer or atomizer.
The compounds of the present invention can be prepared by conventional methods of organic synthesis practiced by those skilled in the art. The general reaction sequences outlined below are general methods useful for preparing the compounds of the present invention and are not meant to be limiting in scope or utility.
Reaction of 2,6-dichloropurine (Formula IV) with various amines of Formula V, many of which are commercially available or prepared by literature methods or modifications of literature methods, in the presence of a polar solvent, such as ethanol, provides purines of Formula VI (General Flowsheet I, infra). Reaction of purines of Formula VI with alkyl halides (R1xe2x80x94Z) in the presence of a base such as potassium carbonate provides N1-alkylated purines of Formula VII. Chloride displacement of N1-alkylated purines of Formula VII with amines, thiols or alcohols of structure Formula VIII, either in neat solution or in an inert solvent such as ethanol or butanol, with or without a base such as sodium hydride as appropriate, at an appropriate temperature provides purines of Formula IX (V=NH, O, S). Transition metal-mediated cross-coupling reaction of purines of Formula IX with boronic acid (R2xe2x80x94B(OH)2) or tin reagents (R2xe2x80x94Sn(n-Bu)3 or R2xe2x80x94SnMe3) provides purines of Formula X (V=NH, O, S). If in Formula X (Y=NH2), then subsequent reaction of Formula X (Y=NH2) with acid chloride (R3COCl), or sulfonyl chloride (R3SO2Cl), or isocyanate (R3NCO), or chloroformate (ClC(O)OR6) reagents provides purines of Formula XI wherein Y=NHC(O)R3, NHSO2R3, or NHC(O)NHR3, or NHC(O)OR6, respectively. On the other hand, if in Formula X, Y already is OR1 or NHC(O)R3 or NHSO2R3 or NHC(O)NHR3 or NHC(O)OR6, as a result of what Y started out as in Formula VIII, then this last step is unnecessary.
Reaction of purines of Formula VII, with alkenyl tin reagents of Formula XII, which are prepared by conventional methods described in the literature, in the presence of a transition metal catalyst, such as Pd(0), provides purines of Formula XIII (General Flowsheet II, infta). Subsequent reaction of purines of Formula XIII with boronic acid (R2xe2x80x94B(OH)2) or tin reagents (R2xe2x80x94Sn(n-Bu)3 or R2xe2x80x94SnMe3) in the presence of a transition metal catalyst, such as Pd(0), provides purines of Formula XV. Alternatively, by switching the order of reactions dependent on the precise reactivity of the purine of Formula VII, reaction of purines of Formula VII with boronic acid (R2xe2x80x94B(OH)2) or tin reagents (R2xe2x80x94Sn(n-Bu)3 or R2xe2x80x94SnMe3) in the presence of a transition metal catalyst, such as Pd(0), provides purines of Formula XIV. Subsequent reaction of purines of Formula XIV, with alkenyl tin reagents of Formula XII, which are prepared by conventional methods described in the literature, in the presence of a transition metal catalyst, such as Pd(0), provides purines of Formula XV. Finally reduction of the olefin within Formula XV provides purines of Formula X (V=CH2).
Definitions of the groups include:
Z=Br;
I;
VI=NH2;
OH;
SH;
R1 are the same or different and independently selected from:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3;
CH(CF3)2;
the combination of X, D, and Q are selected from:
Dxe2x95x90Qxe2x95x90N, and Xxe2x95x90CH;
Dxe2x95x90Xxe2x95x90N, and Qxe2x95x90CH;
Qxe2x95x90Xxe2x95x90N, and Dxe2x95x90CH;
Qxe2x95x90N, and Dxe2x95x90Xxe2x95x90CH;
V=NH;
O;
S;
CH2;
R2 can be in any position on the ring and selected from:
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles including:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl;
4-isoquinolinyl;
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from Br, Cl, F, R1, C(O)CH3;
R3 are the same or different and independently selected from:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh;
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form a 5-8-membered saturated or unsaturated ring;
n1=0-3;
n=0-3;
A=(CH2);
(CH2)2;
(CH2)3;
(OCH2CH2);
(CHCH3);
Y=H;
OR1;
N(R1)2;
N(R1)C(O)R3;
N(R1)C(O)R5;
N(R1)C(O)CH(R6)NH2;
N(R1)SO2R3;
N(R1)C(O)NHR3;
N(R1)C(O)OR6;
R5=C3-C7-cycloalkyl;
R6=C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh;
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2. 
Additional, general non-limiting syntheses of compounds of the present invention of Formula X and Formula XI are shown below in General Flowsheet III. 
Reaction of various amines of Formula V, many of which are commercially available or prepared by literature methods or modifications of literature methods, with boronic acid (R2xe2x80x94B(OH)2) or tin reagents (R2xe2x80x94Sn(n-Bu)3) or (R2xe2x80x94SnMe3) in the presence of a transition metal catalyst, such as Pd(0), provides biaryl amines of Formula XVII. Reaction of 2,6-dichloropurine (Formula IV) with various amines of Formula XVII, in the presence of a polar solvent, such as ethanol, provides purines of Formula XVIII. Reaction of purines of Formula XVIII with alkyl halides (R1xe2x80x94Z) in the presence of a base such as potassium carbonate provides N1-alkylated purines of Formula XIV. Chloride displacement of N1-alkylated purines of Formula XIV with amines, thiols or alcohols of Formula VIII, either in neat solution or in an inert solvent such as ethanol or butanol, with or without a base such as sodium hydride as appropriate, at an appropriate temperature provides purines of Formula X (V=NH, O, S). If in Formula X (Y=NH2), then subsequent reaction of Formula X (Y=NH2) with acid chloride (R3COCl), or sulfonyl chloride (R3SO2Cl), or isocyanate (R3NCO), or chloroformate (ClC(O)OR6) reagents provides purines of Formula XI wherein Y=NHC(O)R3, NHSO2R3, or NHC(O)NHR3, or NHC(O)OR6, respectively. On the other hand, if in Formula X, Y already is OR1 or NHC(O)R3 or NHSO2R3 or NHC(O)NHR3 or NHC(O)OR6, as a result of what Y started out as in Formula VIII, then this last step is unnecessary.
Definitions of the groups include:
Z=Br;
I;
VI=NH2;
OH;
SH;
R1 are the same or different and independently selected from:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3;
CH(CF3)2;
the combination of X, D, and Q are selected from:
Dxe2x95x90Qxe2x95x90N, and Xxe2x95x90CH;
Dxe2x95x90Xxe2x95x90N, and Qxe2x95x90CH;
Qxe2x95x90Xxe2x95x90N, and Dxe2x95x90CH;
Qxe2x95x90N, and Dxe2x95x90Xxe2x95x90CH;
V=NH;
O;
S;
CH2;
R2 can be in any position on the ring and selected from:
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles including:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl;
4-isoquinolinyl;
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from Br, Cl, F, R1, C(O)CH3;
R3 are the same or different and independently selected from:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh;
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form a 5-8-membered saturated or unsaturated ring;
n1=0-3;
n=0-3;
A=(CH2);
(CH2)2;
(CH2)3;
(OCH2CH2);
(CHCH3);
Y=H;
OR1;
N(R1)2;
N(R1)C(O)R3;
N(R1)C(O)R5;
N(R1)C(O)CH(R6)NH2;
N(R1)SO2R3;
N(R1)C(O)NHR3;
N(R1)C(O)OR6;
R5=C3-C7-cycloalkyl;
R6=C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh;
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2.
Additional, general non-limiting syntheses of compounds of the present invention of Formula XVI, Formula XVII and Formula XVIII are shown below in General Flowsheet IV. 
If in Formula X (Y=NH2), then subsequent reaction of Formula X (Y=NH2) with alkyl halide (R8CH2Z), an appropriate base, and a solvent; or reaction of Formula X (Y=NH2) with aldehyde (R8CHO) in the presence of a solvent and a suitable reducing agent provides purines of Formula XVI wherein Y=NHR1, or N(R1)2. On the other hand, if in Formula X, Y already is NHR1, or N(R1)2, as a result of what Y started out as in Formula X, then this last step is unnecessary. If in Formula XVI (Y=NHR1), then subsequent reaction of Formula XVI (Y=NHR1) with acid chloride (R3COCl), or sulfonyl chloride (R3SO2Cl), or isocyanate (R3NCO), or chloroformate (ClC(O)OR6) reagents provides purines of Formula XX wherein Y=NR1C(O)R3, or NR1C(O)R5, or NR1SO2R3, or NR1C(O)NHR3, or NR1C(O)OR6, respectively. On the other hand, if in Formula XVI, Y already is NR1C(O)R3, or NR1C(O)R5, or NR1SO2R3, or NR1C(O)NHR3, or NR1C(O)OR6, as a result of what started out as in Formula XVI, then this last step is unnecessary.
If in Formula X (Y=NH2), then subsequent reaction of Formula X (Y=NH2) with acid (PNHCH(R6)CO2H), in a suitable solvent in the presence of an appropriate coupling agent provides a purine derivative; which upon suitable deprotection provides purines of Formula XIX wherein Y=NHC(O)CH(R6)NH2. On the other hand, if in Formula X, Y already is NHC(O)CH(R6)NH2, as a result of what Y started out as in Formula X, then this last step is unnecessary.
Definitions of the groups include:
Z=Br;
I;
P=C(O)OtBu;
C(O)OCH2Ph;
Fmoc;
Benzyl;
Alloc;
R1 are the same or different and independently selected from:
H;
C1-C6-straight chain alkyl;
C2-C6-straight alkenyl chain;
C3-C6-branched alkyl chain;
C3-C6-branched alkenyl chain;
C3-C7-cycloalkyl;
CH2xe2x80x94(C3-C7-cycloalkyl);
CH2CF3;
CH2CH2CF3;
CH(CF3)2;
the combination of X, D, and Q are selected from:
Dxe2x95x90Qxe2x95x90N, and Xxe2x95x90CH;
Dxe2x95x90Xxe2x95x90N, and Qxe2x95x90CH;
Qxe2x95x90Xxe2x95x90N, and Dxe2x95x90CH;
Qxe2x95x90N, and Dxe2x95x90Xxe2x95x90CH;
V=NH;
O;
S;
CH2;
R2 can be in any position on the ring and selected from:
phenyl;
substituted phenyl, wherein the substituents (1-2 in number) are in any position and are independently selected from R1, OR1, SR1, S(O)R1, S(O2)R1, NHR1, NO2, OC(O)CH3, NHC(O)CH3, F, Cl, Br, CF3, C(O)R1, C(O)NHR1, phenyl, C(O)NHCHR1CH2OH;
1-naphthyl;
2-naphthyl;
heterocycles including:
2-pyridyl;
3-pyridyl;
4-pyridyl;
2-pyrimidyl;
4-pyrimidyl;
5-pyrimidyl;
thiophene-2-yl;
thiophene-3-yl;
2-furanyl;
3-furanyl;
oxazol-2-yl;
oxazol-4-yl;
oxazol-5-yl;
thiazol-2-yl;
thiazol-4-yl;
thiazol-5-yl;
imidazol-2-yl;
imidazol-4-yl;
pyrazol-3-yl;
pyrazol-4-yl;
isoxazol-3-yl;
isoxazol-4-yl;
isoxazol-5-yl;
isothiazol-3-yl;
isothiazol-4-yl;
isothiazol-5-yl;
1,3,4-thiadiazol-2-yl;
benzo[b]furan-2-yl;
benzo[b]thiophene-2-yl;
2-pyrrolyl;
3-pyrrolyl;
1,3,5-triazin-2-yl;
pyrazin-2-yl;
pyridazin-3-yl;
pyridazin-4-yl;
2-quinolinyl;
3-quinolinyl;
4-quinolinyl;
1-isoquinolinyl;
3-isoquinolinyl;
4-isoquinolinyl;
substituted heterocycle, wherein the substituents (1-2 in number) are in any position and are independently selected from Br, Cl, F, R1, C(O)CH3;
R3 are the same or different and independently selected from:
H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh;
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R4=H;
C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
R3 and R4 can be linked together by a carbon chain to form a 5-8-membered saturated or unsaturated ring;
n1=0-3;
n=0-3;
A=(CH2);
(CH2)2;
(CH2)3;
(OCH2CH2);
(CHCH3);
Y=H;
OR1;
N(R1)2;
N(R1)C(O)R3;
N(R1)C(O)R5;
N(R1)C(O)CH(R6)NH2;
N(R1)SO2R3;
N(R1)C(O)NHR3;
N(R1)C(O)OR6;
R5=C3-C7-cycloalkyl;
R6=C1-C4-straight chain alkyl;
C3-C4-branched chain alkyl;
C2-C4-alkenyl chain;
(CH2)nPh;
(CH2)n-substituted phenyl, wherein the phenyl substituents are as defined above in R2;
R8=C1-C5-straight chain alkyl;
C2-C5-straight alkenyl chain;
C2-C5-branched alkyl chain;
C2-C5-branched alkenyl chain;
C3-C7-cycloalkyl;
CF3;
CH2CF3.
The synthesis of compound 5 is shown below in Scheme I. 
The synthesis of compound 11 is shown below in Scheme II. 
The syntheses of compounds 12, 13 and 14 are shown below in Scheme III. 
The syntheses of compound 17 is shown below in Scheme IV. 
The synthesis of compound 17 is shown below in Scheme V. 
The synthesis of compound 25 is shown below in Scheme VI. 
An alternative synthesis of compound 25 is shown below in Scheme VII. 
The synthesis of compound 32 is shown below in Scheme VIII. 
The syntheses of compounds 33 and 34 are shown below in Scheme IX. 
The syntheses of compounds 36, 38, and 40 are shown below in Scheme X. 
The synthesis of compound 43 is shown below in Scheme XI. 
The synthesis of compound 46 is shown below in Scheme XII. 
The syntheses of compound 48 and 50 are shown below in Scheme XIII. 
The synthesis of compound 53 is shown below in Scheme XIV. 
The synthesis of compound 54 is shown below in Scheme XV. 
The synthesis of compound 56 is shown below in Scheme XVI. 
The synthesis of compound 58 is shown below in Scheme XVII. 
The synthesis of compound 60 is shown below in Scheme XVIII. 
The syntheses of compounds 61, and 62 are shown below in Scheme XIX. 
The syntheses of compounds 64, and 65 are shown below in Scheme XX. 
The syntheses of compounds 66, and 67 are shown below in Scheme XXI. 
The synthesis of compound 73 is shown below in Scheme XXII. 
The syntheses of compounds 74, 75, and 76 are shown below in Scheme XXIII. 
The synthesis of compound 77 is shown below in Scheme XXIV. 
The synthesis of compound 78 is shown below in Scheme XXV. 
An alternative synthesis of compound 78, and the synthesis of compound 79 are shown below in Scheme XXVI. 
The synthesis of compound 80 is shown below in Scheme XXVII. 
The synthesis of compounds 86, and 87 are shown below in Scheme XXVIII. 
The synthesis of compound 88 is shown below in Scheme XXIX. 
The syntheses of compounds 93, and 94 are shown below in Scheme XXX. 
The syntheses of compounds 95, and 96 are shown below in Scheme XXXI. 
The synthesis of compound 97 is shown below in Scheme XXXII. 
The syntheses of compounds 98, and 99 are shown below in Scheme XXXIII. 
The synthesis of compound 100 is shown below in Scheme XXXIV. 
The syntheses of compounds 101, and 102 are shown below in Scheme XXXV. 
The syntheses of compounds 103, and 104 are shown below in Scheme XXXVI. 
The syntheses of compounds 106, 107, and 108 are shown below in Scheme XXXVII. 
The syntheses of compounds 109, and 110 are shown below in Scheme XXXVIII. 
The syntheses of compounds 111, and 112 are shown below in Scheme XXXIX. 
The synthesis of compound 113 is shown below in Scheme XL. 
The syntheses of compounds 114, 115, 116, and 117 are shown below in Scheme XLI. 
The syntheses of compound 118 is shown below in Scheme XLII. 
The syntheses of compounds 123 and 124 are shown below in Scheme XLIII. 
The syntheses of compounds 131 and 132 are shown below in Scheme XLIV. 
The syntheses of compounds 134 and 135 are shown below in Scheme XLV. 
The synthesis of compound 137 is shown below in Scheme XLVI. 
The syntheses of compounds 139 and 140 are shown below in Scheme XLVII. 
The synthesis of compound 142 is shown below in Scheme XLVIII. 
The synthesis of compound 144 is shown below in Scheme XLIX. 
The synthesis of compound 146 is shown below in Scheme L. 
The syntheses of compound 148 is shown below in Scheme LI. 
The syntheses of compounds 149-152 are shown below in Scheme LII. 
The syntheses of compounds 153-156 are shown below in Scheme LIII. 
The syntheses of compounds 157-159 are shown below in Scheme LIV. 
The syntheses of compounds 160-163 are shown below in Scheme LV. 
The syntheses of compounds 164-166 are shown below in Scheme LVI. 
The syntheses of compounds 167-168 are shown below in Scheme LVII. 
The syntheses of compounds 169-171 are shown below in Scheme LVIII. 
The syntheses of compounds 172-173 are shown below in Scheme LIX. 
The syntheses of compounds 174-176 are shown below in Scheme LX. 
The syntheses of compounds 177-178 are shown below in Scheme LXI. 
The syntheses of compounds 179-180 are shown below in Scheme LXII. 
The syntheses of compounds 181-182 are shown below in scheme LXIII. 
The syntheses of compounds 187-188 are shown below in Scheme LXIV. 
The syntheses of compounds 193 and 194 are shown below in Scheme LXV. 
The syntheses of compounds 199-200 are shown below in Scheme LXVI. 
The syntheses of compounds 205-206 are shown below in Scheme LXVII. 
The syntheses of compounds 207-210 are shown below in Scheme LXVIII. 
The syntheses of compounds 211-212 are shown below in Scheme LXIX. 
The syntheses of compounds 213-215 are shown below in Scheme LXX. 
The syntheses of compounds 216-217 are shown below in Scheme LXXI. 
The syntheses of compounds 218-219 are shown below in Scheme LXXII. 
The synthesis of compounds 221 is shown below in Scheme LXXIII. 
The synthesis of compound 222 is shown below in Scheme LXXIV. 
The synthesis of compound 223 is shown below in Scheme LXXV. 
The synthesis of compound 224 is shown below in Scheme LXXVI. 
The synthesis of compound 229 is shown below in Scheme LXXVII. 
The syntheses of compounds 230-233 are shown below in Scheme LXXVIII. 
The syntheses of compounds 239-241 are shown below in Scheme LXXIX. 
The syntheses of compounds 242-243 are shown below in Scheme LXXX. 
The syntheses of compounds 248-250 are shown below in Scheme LXXXI. 
The syntheses of compounds 123 and 124 are shown below in Scheme LXXXII. 
The syntheses of compounds 258-260 are shown below in Scheme LXXXIII. 
The syntheses of compounds 261-263 are shown below in Scheme LXXXIV. 
The syntheses of compounds 264-265 are shown below in Scheme LXXXV. 
The synthesis of compound 266 is shown below in Scheme LXXXVI. 